J Hepatol. 2019 Mar 21. pii: S0168-8278(19)30182-5. doi: 10.1016/j.jhep.2019.03.012. [Epub ahead of print]
KLRG1+ natural killer cells exert a novel anti-fibrotic function in chronic hepatitis B.
Wijaya RS1, Read SA2, Schibeci S3, Eslam M3, Azardaryany MK3, El-Khobar K3, van der Poorten D4, Lin R4, Yuen L5, Lam V5, George J6, Douglas MW7, Ahlenstiel G8.
Author information
1
Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia.
2
Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148.
3
Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia.
4
Westmead Hospital, University of Sydney, NSW, Australia.
5
Westmead Hospital, University of Sydney, NSW, Australia; Discipline of Surgery, University of Sydney, Australia.
6
Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Westmead Hospital, University of Sydney, NSW, Australia.
7
Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Westmead Hospital, University of Sydney, NSW, Australia; Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead NSW 2145, Australia.
8
Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148; Blacktown Hospital, Blacktown, NSW 2148, Australia. Electronic address: [email protected].
Abstract
BACKGROUND & AIMS:
Natural killer (NK) cells are known to exert strong antiviral activity. Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is expressed by terminally differentiated NK cells and KLRG1-expressing lymphocytes are known to expand following chronic viral infections. The role of KLRG1 in pathogenesis of chronic hepatitis B (CHB) remains unknown.
METHODS:
Phenotype and function of KLRG1+ NK cells from blood and liver of patients with CHB and healthy individuals was assessed using flow cytometry and in vitro stimulation.
RESULTS:
CHB patients had a higher frequency of KLRG1+ NK cells compared to healthy controls (blood 13.4 vs. 2.3%, p<0.0001 and liver 23.4 vs 2.6%, p<0.01). KLRG1+ NK cells were less responsive to K562 and cytokine stimulation, but demonstrated enhanced cytotoxicity (9 vs. 4.8%, p<0.05) and IFN-γ release (8 vs. 1.5%, p<0.05) via antibody dependent cellular cytotoxicity compared to their KLRG1- counterparts. KLRG1+ NK cells possessed a mature phenotype, demonstrated stronger cytolytic activity and IFN-γ secretion than KLRG1- NK cells against hepatic stellate cells (HSCs). Moreover, KLRG1+ NK cells more effectively induced primary HSCs apoptosis in a TRAIL-dependent manner. Increased KLRG1+ NK cell frequency in liver and blood was associated with lower fibrosis stage (F0/F1) in patients with CHB. Finally, KLRG1+ NK cells had higher expression of CD44 and increased degranulation and IFN-γ production following stimulation with osteopontin, the CD44 ligand, suggesting that HSCs derived osteopontin may cause KLRG1+ NK cells activation.
CONCLUSIONS:
KLRG1+ NK cells likely play an anti-fibrotic role during the natural course of CHB infection. Harnessing this anti-fibrotic function provide a novel therapeutic approach to treat liver fibrosis in CHB.
LAY SUMMARY:
Individuals that are chronically infected with hepatitis B virus (HBV) possess an increased number of immune cells, called natural killer (NK) cells expressing the surface marker KLRG1 in the blood and liver. Here, we demonstrate that these specific NK cells are able to kill activated stellate cells in the liver. Because activated stellate cells contribute to liver scarring, i.e. fibrosis, and subsequent liver dysfunction in individuals with chronic HBV infection, KLRG1+ NK cells are a novel immune cell type that can limit liver scarring.